2020 NIH Chronic GvHD Consensus Project on Criteria for Clinical Trials

November 18–20, 2020

Financial Disclosure

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Dry eyes

Oral lesions

Nail dystrophy

Skin sclerosis

Deep sclerosis

Bronchiolitis obliterans

Loss of bile ducts

Fasciitis/Myositis

Skin ulcers

Manifestations

in cGVHD- 30-60% Incidence

- 15% Life Threatening

INFECTIONS

Chronic GVHD in 2020 - leukemia patients after T-replete haploidentical HCT and PTCy(> 18 years) CIBMTR, 2013-2016

Outcome MAC-BMN=79

MAC-PBN=183

RIC-BMN=192

RIC-PBN=192

p-value

Chronic GVHD 2-years

27% 44% 25% 35% <0.001

Overall Survival2-years

53% 55% 58% 43% 0.07

Im et al, Biol Blood Marrow Transplant 2020; 26:1459

HYPOTHESIS: Better characterization of chronic GVHD and standardization of research tools will lead to better research and ultimately improve clinical outcomes

NIH chronic GVHD consensus project

NIH CGVHD Consensus Conferences 2005 - 2014

Moving from Expert Opinion to Evidence-Based Standards: 13 higly

reference publications in BBMT

0

200

400

600

800

1000

1200

1400

1600

1800

2000

I II III IV V VI

Number ofCitations

NIH Consensus Reports:

• Diagnosis and Staging

• Pathology

• Biomarkers

• Therapeutic Response Criteria

• Ancillary Therapy & Supportive

Care

• Criteria for Clinical Trials

• Biology of CGVHD

Total Scopus

citations: 969

by 1/2020

2005

Consensus

Conference

Total Scopus

citations: 3358

by 1/2020

2014

Consensus

Conference

2017: FDA first drug approval for cGVHD (ibrutinib)

2018: NEJM first chronic GVHD review (Zeiser and Blazar)

Era of development of novel targeted therapies

0

100

200

300

400

500

600

700

1960 1970 1980 1990 2000 2010 2020 2030

Year

Chronic Graft-versus-Host disease publications/year PubMed

since 2004 1st NIH Consensus conference

PubMed, accessed 11/1/2020

2004

2019

First descriptions

CGVHD in man

PBSCT

Georgia Vogelsang

Dr. Alexandra (Lisa) Hult Filipovich, MDJanuary 16, 1951 - May 18, 2020

Internationally recognized leader in bone marrow transplantation and pediatric immunology. She held the Ralph J. Stolle Chair of Pediatric Immunology at Cincinnati Children’s Hospital Medical Center, served as Head of the Division of Immunology at the University of Minnesota Medical School, and was president of the Histiocyte Society. Cincinnati Children’s gained national and international prominence for the treatment of HLH.

Chronic GVHD - where are we in 2020?

• Disease and clinical course are now well characterized

• Complex pathophysiology is much better understood

• Many investigational agents are available for treatment

• Resources are available through industry collaboration

• Regulatory approval pathway has been established

• Ibrutinib has been approved for steroid-refractory disease

Adapted form Paul Martin, lecture to Brazilian BMT Society

Chronic GVHD - where are we in 2020?

• Disease and clinical course are now well characterized

• Complex pathophysiology is much better understood

• Many investigational agents are available for treatment

• Resources are available through industry collaboration

• Regulatory approval pathway has been established

• Ibrutinib has been approved for steroid-refractory disease

BUT• Initial treatment is still calcineurin inhibitor and prednisone

• Best choice of subsequent treatment is still undefined

• No standard approaches to prevention or preemption

• Highly morbid forms of chronic GVHD still exist

Adapted form Paul Martin, lecture to Brazilian BMT Society

Towards the 3rd NIH chronic GVHD consensus conferenceNovember 18 - 20, 2020, NCI

• To implement fundamental changes in research approach to cGVHD treatment and prevention

• Etiology and prevention

• Diagnosis and pre-emptive treatment

• Treatment of established chronic GVHD

• Highly morbid forms of chronic GVHD (lungs, sclerosis)

• Industry and advocacy summit

• Joint ASTCT-NIH-EBMT educational committee

Towards the 3rd NIH chronic GVHD consensus conferenceNovember 18 - 20, 2020, NCI

• To implement fundamental changes in research approach to cGVHD treatment and prevention

• Etiology and prevention

• Diagnosis and pre-emptive treatment

• Treatment of established chronic GVHD

• Highly morbid forms of chronic GVHD (lungs, sclerosis)

• Industry and advocacy summit

• Joint ASTCT-NIH-EBMT educational committee

Vision: To eliminate chronic GVHD as a source of patient suffering

and improve outcomes after allogeneic HCT

2020 CGVHD Consensus Methods

• November 2019 steering committee formed four working groups

• Each working group was organized to encourage global engagement

• Four groups worked individually beginning in February 2020 to review the relevant literature and prepare the initial draft of the manuscript. The Steering Committee reviewed and discussed the initial draft and offered recommendations for revisions.

• Two iterative rounds of comments and revisions were collected before the November 2020 Consensus Conference.

• The manuscripts are further revised for submission in early 2021 after additional suggestions from external reviewers, virtual Conference participants, and a 30-day public comment period.

2020 Chronic GVHD Consensus Process Goals

• What has been accomplished so far

• Gaps

• What should future research address• In next 3 years

• In next 5-7 years

• Four research lanes and 4 WGs

Chronic GVHD Research Lanes – 2020 ConsensusFramework

Intervention based on pre-

transplant characteristics

Intervention based on post-

transplant information

Established chronic GVHD

Severe, advanced chronic GVHD

WG1 WG2 WG3 WG4

Etiology/Prevention Diagnosis/Pre-emptive therapy

Systemic treatment Highly morbid phenotypes

Understanding of biologic processes / efficacy of interventions applied based on risk factors known before transplant, regardless of when the intervention is given

Intervention determined after transplant based on a higher than previously appreciated risk of developing chronic GVHD based on secondary events, signs, symptoms or biomarkers

Systemic treatments for established chronic GVHD, including initial and subsequent therapies

Understanding of the biologic differences in highly morbid phenotypes / local and systemic interventions specifically targeting these morbid conditions

cGVHD manifestations

2020 CGVHD NIH Consensus Steering Committee

• Steven Pavletic, (Bethesda), co-chair

• Kirk Schultz (Vancouver), co-chair

• Daniel Wolff (Regensburg), co-chair

• Stephanie Lee (Seattle), co-chair, lead editor

• Paul Martin (Seattle), lead editor

• Hildegard Greinix (Graz)

• Sophie Paczesny (Charleston, SC)

• Bruce Blazar (Minneapolis)

• Stefanie Sarantopoulos (Durham)

• Joseph Pidala (Tampa)

• Corey Cutler (Boston)

• Gerard Socie (Paris)

• Meredith Cowden (Akron)

• Linda Griffith (Bethesda, ex officio)

2020 CGVHD NIH Consensus Reviewers

• Nicolaus Kroeger, M.D., University of Hamburg• Ryotaro Nakamura, M.D., City of Hope Cancer Center• John DiPersio, M.D., Washington University• George Chen, M.D., University of Rochester • Mark Juckett, M.D., University of Wisconsin• Rafael Duarte, M.D., University Puerta de Hierro Majadahonda• Franco Locatelli, M.D., Università Sapienza, Roma• Areej El-Jawahri, M.D., Massachusetts General Hospital• Robert Soiffer, M.D., Dana Farber Cancer Institute • Daniel Weisdorf, M.D., University of Minnesota • Keith Sullivan, M.D., Duke University• Catherine Lee, University of Utah• Jose Antonio Perez-Simon, M.D., Instituto de Biomedicina de Sevilla • Doris Ponce, M.D. Memorial Sloan-Kettering Cancer Center• Andrew Harris, M.D., University of Utah

NCI Shady Grove, November 2019

3rd NIH CGVHD consensus steering committee

CGVHD Steering Committee Conference Call

November 11, 2020

• “Miracles do not occur at random”

C.D. Bowen